This work represents a 18-year collaboration between the Diabetes Branch and the Institute of Histology and Embryology at the University of Geneva. The initial observations demonstrated that polypeptide hormones are taken up by the cell through a process of receptor-mediated endocytosis similar to other biologically important ligands that bind to cell surface receptors. Several lines of work have been followed in the present project. (a) We have studied the entire process of endocytosis in the diabetic rat, including both receptor-mediated and fluid-phase endocytosis; and (b) We have studied the localization of newly synthesized insulin receptors under conditions of site specific mutagenesis of glycosylation sites.